Treatment of anxiety

ABSTRACT

The invention relates to the use of compounds which act as 5-hydroxytryptamine (5-HT) antagonists at 5-HT &#34;M&#34; receptors in the treatment of anxiety.

This application is a division of application Ser. No. 07/827,511, filedJan. 29, 1992, now U.S. Pat. No. 5,204,356 which is a continuation of07/530,301, filed May 30, 1990, now abandoned; which is a divisional of07/419,728, filed Oct. 11, 1989, now U.S. Pat. No. 4,975,436; which is adivisional of 07/259,719, filed Oct. 19, 1988, now U.S. Pat. No.4,883,803; which is a continuation of 06/888,467, filed Jul. 23, 1986,now abandoned.

This invention relates to a new medical use for certain chemicalcompounds and pharmaceutical compositions containing them, In particularit relates to the use in the treatment of anxiety of compounds which actas antagonists of 5-hydroxytryptamine (5-HT) at receptors known in theart as 5-HT `M` or `M-like` receptors. Such receptors have beendescribed for example by Fozard et al., Eur. J. Pharmacol., 59 (1979),195-210; Ireland, Straughan and Tyers, Br. J. Pharmacol., 75, (1982)16P; Humphrey, Neuropharmacology, 23 (1984). For convenience, we willrefer to them in this specification as 5-HT `M` receptors.

5-HT receptors of this type are located for example on the terminals ofafferent sensory neurones. Compounds which act as antagonists of 5-HT at5-HT `M` receptors may be identified using standard tests, for example,in vivo by measuring their inhibition of the depolarising effect of 5-HTon the rat or rabbit isolated vagus nerve or the rabbit isolated heart,or in vivo by measuring their effect on the Von Bezold-Jarisch reflex(induced by 5-HT) as described for example in the above-mentionedreferences.

A variety of compounds which act as antagonists of 5-HT at 5-HT `M`receptors have been described in the art. The known compounds aregenerally azabicyclo derivatives and/or benzoic acid derivatives.Azabicyclo derivatives include compounds containing a bridged piperidylgroup, such as a tropyl, pseudotropyl, homotropyl or quinuclidinylgroup. An azabicyclo derivative preferably contains a carbocyclic orheterocyclic aromatic group conjugated, for example as an ester oramide, with the azabicyclic ring. The aromatic group may be for examplean optionally substituted phenyl, indolyl, benzofuranyl, benzothienyl orpyrimidinyl group.

Benzoic acid derivatives which act as antagonists of 5-HT at 5-HT `M`receptors include benzoates and benzamides. A benzoic acid derivativemay for example be an ester or an amide formed with an azabicyclic groupas defined above, or formed with a piperidyl group.

Such compounds have been disclosed inter alia in published UK PatentApplications Nos. 2100259, 2125398, 2131420, 2132189 and 2145416 andpublished European Patent Applications 111608, 116255 and 158265. Thecompounds disclosed in published European Patent Application 94742 arealso antagonists of 5-HT at 5-HT `M` receptors. The compounds disclosedin these specifications have been described as being of use in a varietyof conditions, including migraine. However there is no disclosure inthese specifications of compounds which are antagonists of 5-HT at 5-HT`H` receptors being of use in the treatment of anxiety.

Anxiety is widely treated by administering benzodiazepines such asdiazepam, chlordiazepoxide or lorazepam. However the benzodiazepines areknown to cause a number of serious side effects including dependence anddrowsiness.

We have now found that compounds which act as 5-HT antagonists at 5-HT`M` receptors are of use in the treatment of anxiety.

It should be understood that references in this specification totreatment include prophylactic treatment as well as the alleviation ofsymptoms.

Our UK Patent Application No. 2153821A and European Patent ApplicationNo 86300423 disclose tetrahydrocarbazolone derivatives which are potentand selective antagonists of 5-HT-induced responses in the rat isolatedvagus nerve preparation. They can thus be identified as antagonists of5-HT at 5-HT `M` receptors. These tetrahydrocarbazolone derivatives havethe general formula (I) ##STR1## wherein R^(a) represents a hydrogenatom or a C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-(C₁₋₄)alkyl,C₃₋₆ alkenyl, C₃₋₁₀ alkynyl, phenyl or phenyl-(C₁₋₃)alkyl group, and oneof the groups represented by R^(b), R^(c) and R^(d) is a hydrogen atomor a C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₂₋₆ alkenyl or phenyl-(C₁₋₃)alkylgroup and each of the other two groups, which may be the same ordifferent, represents a hydrogen atom or a C₁₋₆ alkyl group; andphysiologically acceptable salts and solyates, e.g. hydrates, thereof.

It is stated in UK Specification No. 2153821A and European PatentApplication 86300423 that the compounds of formula (I) may be usefulinter alia for treating anxiety. The compounds of formula (I) as definedabove are therefore excluded from the presently claimed invention. Thecompounds of formula (I) as defined above are also described and claimedin copending U.S. application Ser. No. 820,743, filed Jan. 22, 1986,which also describes their use, inter alia, for treating anxiety. Theentire disclosure of U.S. application Ser. No. 820,743, filed Jan. 22,1986, is herein incorporated by reference. The compounds of formula (I)as defined above are therefore excluded from the presently claimedinvention, as is the method of treating anxiety using these compoundswhich is included in the copending application.

According to one aspect of the invention, therefore, we provide a methodof treatment of a human or animal subject suffering from or susceptibleto anxiety which comprises administering an effective amount of acompound which acts as an antagonist of 5-HT at 5-HT `M` receptors(excluding compounds of formula (I) as defined above).

Preferred compounds for use in the present invention are azabicycloderivatives (e.g. containing a bridged piperidyl group such as a tropyl,pseudotropyl, homotropyl or quinuclidinyl group) and benzoic acidderivatives (e.g. benzoates and benzamides) which act as antagonists of5-HT at 5-HT `M ` receptors.

Particular mention may be made of the compounds which act as antagonistsof 5-HT at 5-HT `M` receptors disclosed in published British PatentApplications Nos. 2100259, 2125398, 2131420, 2132189 and 2145416 andpublished European Patent Applications Nos. 111608, 116255, 158265 and94742.

A group of compounds described in UK Specification No. 2125398 may berepresented by the general formula (II) ##STR2## wherein R₁ and R₂independently represent hydrogen, halogen, C₁₋₄ alkoxy, hydroxy, amino,C₁₋₄ alkylamino, di(C₁₋₄)alkylamino, mercapto or C₁₋₄ alkylthio;

R₃ represents hydrogen, C₁₋₄ alkyl, C₃₋₅ alkenyl, aryl or aralkyl;

R₄ represents hydrogen, C₁₋₇ alkyl, C₃₋₅ alkenyl or aralkyl;

n is 2 or 3;

the free valence is attached to either fused ring, and the azabicyclicring is in either the exo or endo configurations and acid addition saltsand quaternary ammonium salts thereof.

In the compounds of Formula (II) R₁ and R₂ may, for example,independently represent hydrogen, halogen or C₁₋₄ alkyl, R₃ may be, forexample, hydrogen or C₁₋₇ alkyl and R₄ may be, for example, hydrogen,C₁₋₇ alkyl or aralkyl. The carbonyl group is preferably attached to the3-position of the indole ring. The azabicyclic ring is preferably in theendo configuration.

Compounds described in UK Specifications Nos 2100259 and 2131420 may berepresented by the general Formula (III): ##STR3## wherein R₅ representsC₁₋₄ alkyl, C₁₋₄ alkoxy, or halogen; and

R₆ and R₇ independently represent hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy orhalogen;

provided that (a) when the azabicyclo ring is in the endo configurationand R₇ is hydrogen then R₆ is hydrogen or R₅ and R₆ are both alkyl, and(b) when the azabicyclic ring is in the exo configuration R₅ is a C₁₋₄alkyl group; and pharmaceutically acceptable salts thereof.

Compounds of formula (Ill) in the endo configuration are preferred.

Compounds described in European Specification No 116255 may berepresented by the general formula (IV) ##STR4## wherein R₈ representsC₁₋₄ alkyl;

R₉ represents C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen; and

p is zero or an integer from 1 to 5;

provided that when p is 2 the groups represented by R₉ can be the sameor different and when p is 3, 4 or 5 the groups represented by R₉ arethe same;

and pharmaceutically acceptable salts thereof.

A group of compounds described in European Specification No. 94742 maybe represented by the general formula (V): ##STR5## wherein R₁₀represents a C₁₋₆ alkoxy or amino N-substituted by one or two groupsselected from C₁₋₆ alkyl or C₃₋₈ cycloalkyl or optionally N-substitutedby C₄₋₅ polymethylene;

one of R₁₁, R₁₂ and R₁₃ is hydrogen and the other two are independentlyselected from hydrogen, chloro, bromo, trifluoromethyl, hydroxy, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl and amino;

one of R₁₄ and R₁₅ represents hydrogen, C₁₋₆ alkyl, phenyl or phenylC₁₋₃ alkyl, which phenyl moieties may be substituted by C₁₋₆ alkyl, C₁₋₆alkoxy, CF₃ or halogen, and the other of R₁₄ and R₁₅ is hydrogen or C₁₋₆alkyl;

q is zero or an integer from 1 to 4;

r is zero, or an integer from 1 to 3; and

s is zero, 1 or 2.

Preferred compounds of formula (V) are those wherein R₁₀ is methoxy, R₁₁is hydrogen, R₁₂ is 4-amino, R₁₃ is 5-chloro (relative to the benzamidegroup), R₁₄ and R₁₅ independently represent hydrogen or C₁₋₆ alkyl; q iszero, r is 1 or 2 and s is zero, 1 or 2.

Preferred compounds for use according to the present invention are1αH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate, also known as MDL 72222;1αH, 3α,5αH-tropan-3-yl-3,5-dimethylbenzoate (MDt 72422);(3α-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205-930) and(±)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.3]-non-4-yl)benzamide(BRL 24924).

The invention also provides a pharmaceutical composition which comprisesat least one compound (e.g. an azabicyclo derivative or a benzoic acidderivative) which acts as an antagonist of 5-HT at 5-HT `M` recaptots,for the treatment of anxiety.

In a further aspect the invention provides the use of a compound (e.g.an azabicyclo derivative or a benzoic acid derivative) which acts as anantagonist of 5-HT at 5HT `M` recaptots for the manufacture of amedicanent for the treatment of anxiety.

Pharmaceutical compositions for use according to the present inventionmay be formulated in conventional manner, optionally with one or morephysiologically acceptable carriers or excipients. For example, thecompounds described in the aforementioned patent specifications may beformulated in the manner described therein.

Compounds for use according to the present invention may be formulatedfor oral, buccal, parenteral or rectal administration or in a formsuitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct For constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection e.g. by bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosage:form e.g. in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The compounds of formula (I) may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds of formula (I) may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

For administration by inhalation the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurised packs or a nebuliser, with the useof a suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of a compound offormula (I) and a suitable powder base such as lactose or starch.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration.

The dose at which the compounds may be administered to man will dependupon the route of administration, the body weight of the patient and thepotency of the compounds. For example, the compounds disclosed in theaforementioned patent specifications may be administered at doses in theranges specified therein for the compounds, or at lower doses forexample 0.5 μg to 20 mg e.g. 0.005-20 mg, preferably 0.05-10 mg per unitdose which may be administered, for example, 1 to 4 times per day.

Thus a unit dose of a compound of formula (II) as herein defined maycontain from 0.2 to 250 mg of the active ingredient, and may beadministered for example up to four times per day, such that the overalldaily dose is in the range 0.5 to 500 mg.

A proposed dose of a compound of formula (III) is 0.5 mg to 100 mg e.g.1 to 50 mg of the active ingredient per unit dose, which may beadministered up to four times per day, to give a total daily dose in therange of 0.01 mg/kg to 10 mg/kg, e.g. 0.03 to 3.0 mg/kg

A compound of formula (IV) may be administered in unit doses containingfrom 5 mg to 1000 mg e.g. 10 to 500 mg of the active ingredient, Forexample up to four times daily, such that the overall dally dose is inthe range 0.1 mg/kg to 100 mg/kg e.g. 0.3 to 30 mg/kg.

The following example illustrates a pharmaceutical formulationcontaining (3α-propanyl)-1H-indole-3-carboxylic acid ester for use inthe treatment of anxiety.

Other compounds which are antagonists of 5-HT at 5-HT `M` recaptors maybe formulated in a similar manner.

    ______________________________________                                        Capsules          mg/capsule                                                  ______________________________________                                        Active Ingredient 0.5                                                         * Starch 1500     98.5                                                        Magnesium Stearate BP                                                                           1.0                                                         Fill Weight       100.00                                                      ______________________________________                                         * a form of directly compressible starch.                                

The active ingredient is sieved and blended with the excipients. The mixis filled into size No. 2 hard gelatin capsules using suitablemachinery. Other doses may be prepared by altering the fill weight andif necessary changing the capsule size to suit.

The anxiolytic activity of compounds for use according to the presentinvention has been demonstrated in the rat social interaction test.

Rat Social Interaction Test

Social interaction in pairs of male rats is reduced by aversive stimulisuch as unfamiliar territory and bright light. (Social interaction isactive social contact e.g. sniffing, following, crawling under and over,boxing and fighting); Reduced social interaction can be prevented byanxiolytic agents. Thus, the anxiolytic activity of a compound can beevaluated by measuring its effect on the behaviour of rats subject tosuch aversive conditions.

The test procedure used was based on that described by S. File (J.Neuroscience Methods, Vol. 2, 219-238, 1980; and Recent Advances inNeuropsychopharmacology, Vol. 31, 241-251, 1981).

Test Compounds

(A) (3α-tropanyl)-1H-indole-3-carboxylic acid ester

B) 1αH, 3α, 5αH-tropan-3-yl-3,5-dichlorobenzoate

Test Procedure

Male Hooded Lister rats (100-140 g) were kept in cages of 5 under lowlight for at least 4 days before testing. Individual rats were thentaken from cages distant from each other and the test compoundsadministered orally (as a suspension in 5% acacia solution).

Control animals received acacia solution.

Diazepam was administered to some animals in place of the test compound,as a standard.

Following dosing, the animals were placed in individual cages for 1hour. They were then moved to an enclosed test arena (61×61×41 cm high)illuminated by two overhead strip lights to provide a high lightintensity. The rats were observed and the amount of time that the pairsof rats spent in active social contact was recorded with a stop-watchover a 10 minute test period. Their behaviour was also monitored andrecorded via a camera above the test arena. Locomotor activity of therats was measured automatically by recording the number of light beamcrossings which occurred in the 10 minute test period.

Results

Diazepam

Minimum effective dose: 500 μg/kg (Oral).

    ______________________________________                                        Test     Dose range tested                                                                           Minimum effective Dose*                                Compound (μg/kg) oral                                                                             (μg/kg) oral                                        ______________________________________                                        A        0.01-100      0.01                                                   B          1-100       10                                                     ______________________________________                                         * The minimum effective dose of the test compound is the dose required to     produce a significant increase in social interaction as compared with the     control animals (p = <0.05).                                             

At doses of 4 mg/kg (orally) and above the effect of diazepam on socialinteraction is masked by sedation, as indicated by a reduction inlocomotor activity.

The test compounds produced no reduction in locomotor activity or anyother adverse effect up to the highest doses tested, i.e. 100 μg/kg.

I claim:
 1. A method of treatment of anxiety in a human or animalsubject suffering from anxiety which comprises administering aneffective amount of a compound which acts as an antagonist of5-hydroxytryptamine (5-HT) at 5-HT "M" receptors, excludingtetrahydrocarbazolone derivatives of the general formula (I) ##STR6##wherein R^(a) represents a hydrogen atom or a C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyl-(C₁₋₄)alkyl, C₃₋₆ alkenyl, C₃₋₁₀ alkynyl,phenyl or phenyl-(C₁₋₃)alkyl group, and one of the groups represented byR^(b), R^(c) and R^(d) is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl or phenyl-(C₁₋₃)alkyl group and each of theother two groups, which may be the same or different, represents ahydrogen atom or a C₁₋₆ alkyl group;and physiologically acceptable saltsand solvates thereof.
 2. The method according to claim 1 wherein saidcompound which acts as an antagonist of 5-HT at 5-HT "M" receptors isselected from the group consisting of azabicyclo derivatives and benzoicacid derivatives.
 3. The method according to claim 2 wherein saidazabicyclo derivative contains a bridged piperidyl group such as atropyl, pseudotropyl, homotropyl or quinuclidinyl group.
 4. The methodaccording to claim 2 wherein said benzoic acid derivative is selectedfrom the group consisting of benzoate and benzamide derivatives.
 5. Themethod according to claim 1 wherein said compound which acts as anantagonist of 5-HT at 5-HT "M" receptors is a compound of formula (III)##STR7## wherein R₅ represents C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen; andR₆and R₇ independently represent hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy orhalogen; provided that (a) when the azabicyclo ring is in the endoconfiguration and R₇ is hydrogen then R₆ is hydrogen or R₅ and R₆ areboth alkyl, and (b) when the azabicyclic ring is in the exoconfiguration R₅ is a C₁₋₄ alkyl group; or a pharmaceutically acceptablesalt thereof.
 6. The method according to claim 5 wherein said azabicycloring is in the endo configuration.
 7. The method according to claim 1wherein said compound which acts as an antagonist of 5-HT at 5-HT "M"receptors is a compound of formula (IV) ##STR8## wherein R₈ representsC₁₋₄ alkyl;R ₉ represents C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen; and p iszero or an integer from 1 to 5;provided that when p is 2 the groupsrepresented by R₉ can be the same or different and when p is 3, 4 or 5the groups represented by R₉ are the same; or a pharmaceuticallyacceptable salt thereof.
 8. A method according to claim 1 wherein saidcompound acts as an antagonist of 5-HT at 5-HT "M" receptors is selectedfrom the group consistingof:1αH,3α,5αH-tropan-3-yl-3,5-dichlorobenzoate; and1αH,3α,5αH-tropan-3-yl -3,5-dimethylbenzoate.
 9. A method of treatmentof anxiety in a human or animal subject suffering from anxiety whichcomprises administering to the human or animal subject an effectiveamount of a compound which acts as an antagonist of 5-hydroxytryptamine(5-HT) at 5-HT "M" receptors, wherein the compound is1αH,3α,5αH-tropan-3-yl-3,5-dimethylbenzoate.